WO2003055878A1 - Amides d'acide 2-heteroarylcarboxylique - Google Patents

Amides d'acide 2-heteroarylcarboxylique Download PDF

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Publication number
WO2003055878A1
WO2003055878A1 PCT/EP2002/014288 EP0214288W WO03055878A1 WO 2003055878 A1 WO2003055878 A1 WO 2003055878A1 EP 0214288 W EP0214288 W EP 0214288W WO 03055878 A1 WO03055878 A1 WO 03055878A1
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WIPO (PCT)
Prior art keywords
mmol
oct
amino
benzothiophene
theory
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PCT/EP2002/014288
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German (de)
English (en)
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WO2003055878A8 (fr
Inventor
Martin Hendrix
Frank-Gerhard BÖSS
Christina Erb
Timo Flessner
Marja Van Kampen
Joachim Luithle
Christoph Methfessel
Welf Burkhard Wiese
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Bayer Healthcare Ag
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Application filed by Bayer Healthcare Ag filed Critical Bayer Healthcare Ag
Priority to CA2471593A priority Critical patent/CA2471593C/fr
Priority to DE50209614T priority patent/DE50209614D1/de
Priority to US10/500,096 priority patent/US7732477B2/en
Priority to AU2002358718A priority patent/AU2002358718A1/en
Priority to EP02793023A priority patent/EP1461335B1/fr
Publication of WO2003055878A1 publication Critical patent/WO2003055878A1/fr
Publication of WO2003055878A8 publication Critical patent/WO2003055878A8/fr
Priority to US12/777,764 priority patent/US8076355B2/en
Priority to US13/289,346 priority patent/US8884017B2/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the invention relates to new 2-heteroarylcarboxamides, processes for their preparation and their use for the manufacture of medicaments for the treatment and / or prophylaxis of diseases and for improving perception, concentration, learning and or memory.
  • Nicotinic acetylcholine receptors form a large family of ion channels that are activated by the body's own messenger substance acetylcholine
  • nAChR nAChR consists of five subunits, which can be different (certain combinations of ⁇ l-9 and ßl-4, ⁇ , ⁇ , ⁇ subunits) or identical ( ⁇ 7-9). This leads to the formation of a variety of subtypes that show a different distribution in the muscles, nervous system and other organs
  • nAChR neuropeptide acetylcholine receptors
  • Activation of nAChR leads to the influx of cations into the cell and the stimulation of nerve or muscle cells.
  • Selective activation of individual nAChR subtypes limits this stimulation to the cell types that have the corresponding subtype and can thus have undesirable side effects such as avoid stimulating nAChR in the muscles.
  • Clinical experiments with nicotine and experiments in various animal models indicate a role of central nicotinic acetylcholine receptors in learning and memory processes (e.g. Rezvani and Levin, Biol. Psychialry 2001, 49, 258-267).
  • Nicotinic acetylcholine receptors of the alpha7 subtype (7-nAChR) have a particularly high concentration in brain regions important for learning and memory, such as the hippocampus and the cerebral cortex (Seguela et al., J Neurosci. 1993, 13, 596- 604).
  • the ⁇ 7-nAChR has a particularly high permeability to calcium ions, increases glutamatergic neurotransmission, influences the growth of neurites and in this way modulates neuronal plasticity (Broide and Leslie, Mol.
  • N- (aza-bicycloalkyl) heteroarylcarboxamides in particular N- (l-aza-bicyclo-
  • JP 14030084A discloses 1-azabicycloalkanes and their action on the nicotinic ⁇ 7 receptor.
  • the present invention relates to compounds of the formula (I)
  • R 1 represents l-aza-bicyclo [2.2.2] oct-3-yl
  • R 2 represents hydrogen or dC 6 alkyl
  • R 3 represents hydrogen, halogen or -CC 6 alkyl
  • A represents oxygen or sulfur
  • the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
  • the invention relates to both the enantiomers or diastereomers or their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.
  • the compounds according to the invention can also be present in the form of their salts, solvates or solvates of the salts.
  • preferred salts are physiologically acceptable salts of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds according to the invention can be acid addition salts of the compounds with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, bromine hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • salts with customary bases can also be mentioned as salts, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, Procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1-ephenamine or N-methylpiperidine.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example calcium or magnesium salts
  • ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, Procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1-ephenamine or
  • solvates are those forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of
  • CrC 6 - and -C-C 4 alkoxy represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms.
  • methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • dC 6 - and -CC 4 alkyl represent a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms.
  • a straight-chain or branched alkyl radical having 1 to 4, particularly preferably 1 to 3, carbon atoms is preferred.
  • the following may be mentioned: methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • (-C-C 6 ) alkanoyl stands for a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, which carries a double-bonded oxygen atom in the 1 position and is linked via the 1 position.
  • a straight-chain or branched alkanoyl radical having 1 to 4, particularly preferably having 1 to 2, carbon atoms is preferred. Examples that may be mentioned are: formyl, acetyl, propionyl, n-butyryl, isobutyryl, pivaloyl and n-hexanoyl.
  • Ci-C ⁇ -Alkylamino stands for a straight-chain or branched alkylamino radical with 1 to 6 carbon atoms, preferably with 1 to 4, particularly preferably with 1 to
  • Non-limiting examples include methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.
  • (-C 6 -Acylamino stands for an amino group with a straight-chain or branched alkanoyl substituent which has 1 to 6 carbon atoms and via the
  • Carbonyl group is linked.
  • An acylamino radical having 1 to 4, particularly preferably having 1 to 2, carbon atoms is preferred. Examples include and are preferably: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.
  • Non-limiting examples include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino.
  • Arylsulfonylamino represents a naphthyl or phenylsulfonylamino radical and preferably a phenylsulfonylamino radical.
  • C 1 -C 6 alkylthio represents a straight-chain or branched alkylthio radical having 1 to 6 carbon atoms.
  • Arylcarbonyl represents a naphthyl or phenylcarbonyl radical and preferably a phenylcarbonyl radical (benzoyl radical).
  • Heteroarylcarbonyl stands for a heteroarylcarbonyl radical with a 5- to 6-membered, preferably 5-membered heteroaryl ring with up to 2 heteroatoms selected from the group O, S and N.
  • Non-limiting examples include thienylcarbonyl, furylcarbonyl, pyrrolylcarbonyl, thiazolylcarbonyl, oxazolyl carbonyl, imidazolylcarbonyl, pyridylcarbonyl, pyrimidylcarbonyl.
  • Non-limiting examples include cyclopropylcarbonylmethyl,
  • Halogen stands for fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred. Fluorine and chlorine are particularly preferred.
  • radicals in the compounds according to the invention are optionally substituted, the radicals, unless otherwise specified, can be substituted one or more times in the same or different manner. A substitution with up to three identical or different substituents is preferred.
  • R 1 represents l-aza-bicyclo [2.2.2] oct-3-yl
  • R 2 represents hydrogen or (CC 6 ) alkyl
  • R 3 represents hydrogen, halogen or (C i -C 6 ) alkyl
  • A represents oxygen or sulfur
  • Halogen, formyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, formamido, acetamido, (C ⁇ -C 6 ) alkyl, (C ⁇ -C 6 ) alkoxy, (C ⁇ -C 6 ) alkylthio and benzo are substituted.
  • R 1 represents l-aza-bicyclo [2.2.2] oct-3-yl
  • R 2 represents hydrogen
  • R 3 represents hydrogen, chlorine, fluorine or methyl
  • A represents oxygen or sulfur
  • ring B for benzo or pyrido benzo or pyrido, benzo or pyrido optionally being selected from 1 to 3 radicals from the group consisting of hydrogen, halogen,
  • R 1 represents l-aza-bicyclo [2.2.2] oct-3-yl
  • R 2 represents hydrogen or C i -C 6 alkyl
  • R 3 represents hydrogen, halogen or -CC 6 alkyl
  • A represents oxygen or sulfur
  • Ci-Cö-alkylthio Ci-Cö-alkylamino
  • heteroarylcarbonylamino arylcarbonylamino
  • C ⁇ -C 4 -alkylsulfonylamino di- (arylsulfonyl) amino, C -
  • R 1 represents l-aza-bicyclo [2.2.2] oct-3-yl
  • R 2 represents hydrogen
  • R 3 represents hydrogen, chlorine, fluorine or methyl
  • A represents oxygen or sulfur
  • Trifluoromethoxy nitro, amino, formamido, acetamido, methyl, ethyl, methoxy, ethoxy, C 1 -C 4 alkylamino, furylcarbonylamino, phenylcarbonylamino, methylsulfonylamino, di- (phenylsulfonyl) amino, cyclopropylcarbonylmethyl or amino (hydroxyimino) rnet ,
  • R 1 represents (3R) -l-aza-bicyclo [2.2.2] oct-3-yl
  • R 2 represents hydrogen
  • R 3 represents hydrogen, chlorine, fluorine or methyl
  • A represents oxygen or sulfur
  • R 1 represents (3R) -l-aza-bicyclo [2.2.2] oct-3-yl
  • R 2 , R 3 , A and the ring B have the meanings given above.
  • R 1 represents (3R) -l-aza-bicyclo [2.2.2] oct-3-yl
  • R 2 , R 3 , A and Z have the meanings given above.
  • R 2 represents hydrogen or methyl, 1 "and R, R, A and the ring B have the meanings given above.
  • R 2 represents hydrogen
  • R 1 , R 3 , A and the ring B have the meanings given above.
  • R> 3 represents hydrogen, fluorine, chlorine or methyl
  • R 1 , R 2 , A and the ring B have the meanings given above.
  • R represents hydrogen or methyl
  • R 1 , R 2 , A and the ring B have the meanings given above.
  • R stands for hydrogen. and R 1 , R 2 , A and the ring B have the meanings given above.
  • A stands for sulfur
  • R 1 , R 2 , R 3 and the ring B have the meanings given above.
  • A stands for oxygen
  • R 1 , R 2 , R 3 and the ring B have the meanings given above.
  • A stands for sulfur
  • R, R, R and Z have the meanings given above.
  • R, R, R and Z have the meanings given above.
  • the ring B represents benzo or pyrido, benzo and pyrido optionally being selected from 1 to 3 radicals from the group consisting of hydrogen, halogen,
  • R 1 , R 2 , R 3 and A have the meanings given above.
  • the ring B represents benzo or pyrido, benzo and pyrido optionally being selected from 1 to 3 radicals from the group consisting of hydrogen, halogen,
  • R 1 , R 2 , R 3 and A have the meanings given above.
  • ring B stands for benzo, benzo optionally being selected from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, and 1 to 3 radicals,
  • R 1 , R 2 , R 3 and A have the meaning given above.
  • R 1 , R 2 , R 3 and A have the meanings given above.
  • R 1 represents (3R) -l-aza-bicyclo [2.2.2] oct-3-yl
  • R 2 and R 3 represent hydrogen
  • A stands for sulfur
  • the ring B represents benzo or pyrido, benzo and pyrido optionally being substituted by 1 to 3 radicals selected from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, formamido, acetamido and (C 1 -C 4 ) -alkyl are.
  • the invention further relates to processes for the preparation of the compounds of the formula (I), characterized in that compounds of the general formula (II)
  • X represents hydroxy or a suitable leaving group, in an inert solvent, if appropriate in the presence of a condensing agent and if appropriate in the presence of a base.
  • X is a leaving group
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
  • Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, dimethyl sulfoxide, acetonitrile or pyridine, preference is given to tetrahydrofuran, dimethylformamide or chloroform.
  • Condensing agents are, for example, carbodiimides such as, for example, N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylamino-isopropyl) -N' -ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3 sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines, e.g. Triethylamine, N-methylmo ⁇ holin, N-methylpiperidine, 4-N, N-dimethylaminopyridine or N, N-diisopropylethylamine.
  • alkali carbonates e.g. Sodium or potassium carbonate
  • hydrogen carbonate e.g. Triethylamine, N-methylmo ⁇ holin, N-methylpiperidine, 4-N, N-dimethylaminopyridine or N, N-diisopropylethylamine.
  • EDC '-ethylcarbodiimide hydrochloride
  • HOBt 1-hydroxybenzotriazole
  • the process according to the invention is preferably carried out in a temperature range from room temperature to 50 ° C. at normal pressure.
  • the compounds of the general formula (I) according to the invention are suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and / or animals.
  • the compounds according to the invention show an unforeseeable, valuable spectrum of pharmacological activity.
  • They are characterized as ligands, especially agonists on the ⁇ 7-nAChR.
  • the compounds according to the invention can be used alone or in combination with other medicaments for the treatment and / or prevention of cognitive disorders, in particular Alzheimer's disease. Because of their selective action as ⁇ 7-nAChR agonists, the compounds according to the invention are particularly suitable for improving perception, concentration, learning, or memory, in particular after cognitive disorders, as described, for example, in
  • Situations / diseases / syndromes such as "mild cognitive impairment", age-related learning and memory disorders, age-associated memory loss, vascular dementia, traumatic brain injury, stroke, dementia that occurs after strokes ("post stroke dementia"), post-traumatic Traumatic brain injury, general concentration disorders, concentration disorders in children with learning and memory problems, Attention Deficit Hyperactivity Disorder, Alzheimer's disease, dementia with Lewy bodies, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, Progressive nuclear palsy, dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia, schizophrenia with dementia or Korsakoff psychosis.
  • ALS amyotrophic lateral sclerosis
  • the compounds according to the invention can be used alone or in combination with other medicaments for the prophylaxis and treatment of acute and / or chronic pain (for a classification see "Classification of Chronic Pain, Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms", 2nd ed ., Meskey and Begduk, eds .; LASP-Press, Seattle, 1994), in particular for the treatment of cancer-induced pain and chronic neuropathic pain, such as, for example, in diabetic neuropathy, posthephetic neuralgia, peripheral nerve damage, central pain (for example as a result cerebral ischemia) and trigeminal neuralgia, and other chronic pain such as lumbago, low back pain or rheumatic pain.
  • cancer-induced pain and chronic neuropathic pain such as, for example, in diabetic neuropathy, posthephetic neuralgia, peripheral nerve damage, central pain (for example as a result cerebral ischemia) and trigeminal neuralgia, and other chronic pain such as lumbag
  • these substances are also suitable for the therapy of primary acute pain of any genesis and the secondary pain states resulting therefrom, as well as for the treatment of chronic, formerly acute pain states.
  • the [ 3 H] methyllycaconitine binding assay is a modification of that described by Davies et al.
  • Rat brain tissue (hippocampus or whole brain) is in homogenization buffer (10% w / v) (0.32 M sucrose, 1 mM EDTA, 0.1 mM phenylmethylsulfonyl fluoride
  • the P2 pellet is washed twice with binding buffer (50 mM Tris-HCl, 1 mM MgCl 2 , 120 mM NaCl, 5 mM KC1, 2 mM CaCl 2 , pH 7.4) and centrifuged (15,000 xg, 4 ° C, 30 min) ,
  • the P2 membranes are resuspended in binding buffer and incubated in a volume of 250 ⁇ l (membrane protein amount 0.1-0.5 mg) for 2.5 h at 21 ° C. in the presence of 1-5 nM [ 3 H] -methyllycaconitine, 0.1% (w / v) BSA (bovine serum albumin) and various concentrations of the test substance.
  • the non-specific binding is determined by incubation in the presence of 1 ⁇ M ⁇ -bungaro toxin or 100 ⁇ M nicotine or 10 ⁇ M MLA (methyl lycaconitine).
  • the incubation is ended by adding 4 ml of PBS (20 mM Na 2 HPO 4 , 5 mM KH 2 PO 4 , 150 mM NaCl, pH 7.4, 4 ° C) and filtration through type A / E glass fiber filters (Gelman Sciences) which had previously been immersed in 0.3% (v / v) polyethyleneimine (PEI) for 3 h.
  • PBS polyethyleneimine
  • the filters are washed twice with 4 ml of PBS (4 ° C.) and the bound radioactivity is determined by scintillation measurement. All tests are carried out in triplicate. From the IC 50 value of the compounds (concentration of the test substance at which 50% of the ligand bound to the receptor is displaced), the dissociation constant K D and the concentration L of
  • the object recognition test is a memory test. It measures the ability of rats (and mice) to distinguish between known and unknown objects.
  • Observation arena faced with two identical objects. The rat will examine both objects extensively, i.e. sniff and touch. In a second round, after a waiting time of 24 hours, the rat is again placed in the observation arena. Now one of the known objects has been replaced by a new, unknown object. If a rat recognizes the known object, it will primarily examine the unknown object. After 24 hours, however, a rat has usually forgotten which object it has already examined in the first run and will therefore inspect both objects to the same extent. The administration of a substance with a learning and memory-improving effect will lead to the fact that a rat saw what was seen 24 hours before, in the first round
  • a discrimination index means that the rat examines both objects, the old and the new, at the same time; ie it has not recognized the old object and reacts to both objects as if they were unknown and new.
  • a discrimination index greater than zero means that the rat inspects the new object longer than the old one; ie the rat recognized the old object.
  • the social recognition test is a test to test the learning or memory-improving effects of test substances.
  • Rat rats which are kept in groups, are placed individually in test cages 30 minutes before the start of the test.
  • the test animal is placed in an observation box four minutes before the start of the test.
  • a juvenile animal is added to the test animal and the time taken for the adult animal to examine the juvenile animal is measured for 2 minutes (trial 1). All behaviors clearly directed towards the young animal are measured, i.e. anogenital inspection, tracking and grooming, in which the old animal has a maximum distance of 1 cm from the young animal.
  • the juvenile animal is then removed and the adult is left in its test cage
  • test substance (with 24 hour retention, the animal is returned to its home cage).
  • the adult test animal is treated with test substance.
  • learning or storing information about the young animal can be influenced by the substance.
  • the test is repeated (Trial 2). The bigger the test
  • the compounds of general formula (I) according to the invention are suitable for use as medicaments for humans and animals.
  • the present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, contain one or more compounds of the general formula (I) or which consist of one or more compounds of the formula (I), and processes for the preparation of these preparations.
  • the compounds of the formula (I) should be present in these preparations in a concentration of 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight, of the total mixture.
  • the pharmaceutical preparations can also contain other active pharmaceutical ingredients.
  • the pharmaceutical preparations listed above can be prepared in a customary manner by known methods, for example using the excipient or excipients.
  • the new active ingredients can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.
  • the application is carried out in the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously. However, it can also be done by inhalation via the mouth or nose, for example with the aid of a spray, or topically via the skin. In general, it has proven to be advantageous to administer amounts of approximately 0.001 to 10 mg / kg, preferably approximately 0.005 to 3 mg / kg of body weight in the case of oral use in order to achieve effective results.
  • UV detector 3000HR 210 nm
  • LC-MS Method F Instrument: Micromass Quattro LCZ, HP 1100; Column: Symmetry C18, 50 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; Gradient: 0.0 min 90% A - 4.0 min 10% A -_ 6.0 min 10% A; Oven: 40 ° C; Flow: 0.5 ml / min; UN detection: 208-400 nm.
  • Device type MS Micromass ZQ
  • Device type HPLC Waters Alliance 2790; Column: Uptisphere C18, 50 mm x 2.0 mm, 3.0 ⁇ m; Eluent A: acetonitrile + 0.05% formic acid, eluent B: water + 0.05% formic acid; Gradient: 0.0 min 5% A -> 2.0 min 40% A -_ 4.5 min 90% A - »5.5 min 90% A; Oven: 45 ° C; Flow: 0.0 min 0.75 ml / min -_ * 4.5 min 0.75 ml / min -_ * 5.5 min 1.25 ml / min; UN detection: 210 nm.
  • HPLC method H HPLC method H:
  • reaction mixture (0.92-1.00 M solution) is added slowly to the reaction mixture in such a way that the temperature of the reaction mixture does not rise above 0 ° C.
  • the mixture is stirred at 0 ° C. for 45 minutes.
  • 60-65 equivalents of ice-cooled 50% hypophosphoric acid are also added dropwise to the reaction mixture in such a way that the temperature does not rise above 0 ° C.
  • the mixture is left to stir at -5 ° C. for one hour before being placed in the refrigerator overnight.
  • the reaction mixture is diluted with sodium bicarbonate solution and ethyl acetate and sodium bicarbonate is added in portions until the reaction is basic. The workup is described using the examples below.
  • the synthesis is carried out according to the general working instructions; For working up, the precipitate formed is suction filtered and washed out several times with water, ethyl acetate and THF. The organic phases of the filtrates obtained are separated off, the aqueous phase is washed with ethyl acetate and the combined organic phases are dried and concentrated.
  • the product obtained is purified by means of preparative HPLC. Starting from 2.40 g (11.53 mmol) of 3-aminothieno [3,2-b] pyridine-2-carboxylic acid methyl ester 2.54 g (36.88 mmol) of sodium nitrite 0.12 g (5% of theory) of the desired product.
  • the synthesis is carried out according to the general working instructions; for working up, the aqueous phase is shaken twice with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried and the solvent is removed in vacuo. Starting from 84 mg
  • the synthesis is carried out according to the general working instructions; for working up, the precipitated solid is filtered off, washed with water and acetonitrile and dried in vacuo. Starting from 115 mg (0.60 mmol) of thieno [3,2-b] pyridine-2-carboxylic acid methyl ester, 77 mg (72% of theory) of the desired product are obtained.
  • reaction is carried out with 0.90 g (22.7 mmol) of sodium hydride (60%) and 1.76 g (16.6 mmol) of methyl mercaptoacetate in accordance with the general test instructions.
  • the reaction product obtained is first purified by column chromatography on silica gel (mobile solvent: dichloromethane / methanol 100: 1), then dissolved in 30 ml of pyridine and mixed with 650 ⁇ l (8.4 mmol) of methanesulfonic acid chloride. The mixture is stirred at 80 ° C for 2 h.
  • Potassium carbonate submitted. 1.75 g (16.15 mmol) of methyl chloroacetate are added. The reaction mixture is heated to 130 ° C. for 4 h and then cooled to 0 ° C. using an ice bath. 27 ml of THF, 2.59 g (46.14 mmol) of potassium hydroxide and 27 ml of water are added. The mixture is stirred at RT overnight. The solvent is removed under reduced pressure. It is diluted with water and with conc. Hydrochloric acid acidified. It is extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is reduced under reduced pressure on a rotary Evaporator removed.
  • the raw product is used without further purification.
  • HATU, 369.8 mg (2.86 mmol) N, N-diisopropylethylamine and 1.5 ml DMF are reacted according to the general working procedure (variant A).
  • the reaction mixture is purified by preparative HPLC.
  • the product is dissolved in acetonitrile and an excess of 1 N salic acid is added. Finally the solvent is removed. 175 mg (84%> of theory) of the title compound are isolated.
  • Example 1 The experiment is carried out in the same manner and dimension as described in Example 1 with S-3-aminoquinuclidine dihydrochloride. 174 mg (83%> of theory) of the title compound are isolated. The analytical data correspond to those of the enantiomeric compound from Example 1.
  • Example 4 The experiment is carried out in the same manner and dimension as described in Example 4, with S-3-aminoquinuclidine dihydrochloride. 117 mg (75% of theory) of the title compound are isolated. The analytical data agree with that of the enantiomeric compound from Example 4.
  • Example 6 The experiment is carried out in the same manner and dimension as described in Example 6 with S-3-aminoquinuclidine dihydrochloride. 38 mg (68% of theory) of the title compound are isolated. The analytical data agree with that of the enantiomeric compound from Example 6.
  • Example 19 The experiment is carried out in the same manner and dimension as in Example 19, but using S-3-aminoquinuclidine dihydrochloride. 180 mg (54% of theory) of the title compound are isolated. The analytical data correspond to those of the enantiomeric compound from Example 19.
  • Example 23 The experiment is carried out in the same manner and dimension as for the compound from Example 21, but using S-3-aminoquinuclidine dihydrochloride. 216 mg (58% of theory) of the title compound are isolated. The analytical data correspond to those of the enantiomeric compound from Example 21.
  • Example 23
  • Example 27 The experiment is carried out in the same manner and dimension as for the compound from Example 25, but using S-3-aminoquinuclidine dihydrochloride. 100 mg (30% of theory) of the title compound are isolated. The analytical data correspond to those of the enantiomeric compound from Example 25.
  • Example 27
  • Phases are dried over magnesium sulfate and the solvent removed under reduced pressure on a rotary evaporator.
  • the crude product is taken up in methanol and together with acidic ion exchange resin (Dowex WX2-200) for about 20 min. long shaken.
  • the loaded ion exchanger is washed three times with 30 ml of methanol, then with water / methanol 8: 2, again with methanol, with dichloromethane and finally again with methanol.
  • the product is eluted with methanol / triethylamine 95: 5.
  • the solvent is removed on the rotary evaporator under reduced pressure. 52 mg (58% of theory) of the title compound are isolated.
  • the loaded ion exchanger is washed three times with 30 ml of methanol, then with water / methanol 8: 2, again with methanol, with dichloromethane and finally again with methanol.
  • the product is eluted with methanol / triethylamine 95: 5.
  • the solvent is removed under reduced pressure on a rotary evaporator and 20 ml of 1 N aqueous sodium hydroxide solution are added to the crude mixture.
  • the aqueous phase is extracted six times with 20 ml of ethyl acetate.
  • the combined organic phases are dried over magnesium sulfate and freed from the solvent on a rotary evaporator under reduced pressure. 100.7 mg (82% of theory) of the title compound are isolated.
  • the analytical data agree with that of the enantiomeric compound from Example 32.
  • the product is taken up in 100 ml of 1N aqueous sodium hydroxide solution and extracted three times with 50 ml each of ethyl acetate. The combined organic phases are dried over magnesium sulfate and freed from the solvent on a rotary evaporator under reduced pressure.
  • the reaction mixture is taken up in methanol and together with acidic ion exchange resin (Dowex WX2-200) for about 40 min. long stirred.
  • the loaded ion exchanger is washed six times with 100 ml of methanol.
  • the mixture is then eluted with methanol / triethylamine 99: 1 to 90:10.
  • the solvent is removed under reduced pressure. It is dried over magnesium sulfate. 1.75 g (99% of theory) of the title compound are isolated.
  • the product comes with 95: 5 eluted.
  • the solvent is removed on the rotary evaporator under reduced pressure.
  • the crude product is purified on silica gel 60 (mobile phase: dichloromethane / triethylamine 100: 1 - dichloromethane / methanol / triethylamine 100: 1: 1 -> dichloromethane / methanol / triethylamine 90: 10: 1). 643 mg (46% of theory) of the title compound are isolated.
  • the aqueous phase is extracted with ethyl acetate and washed with saturated sodium chloride solution.
  • the combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure on a rotary evaporator.
  • the crude product is taken up in methanol and together with acidic ion exchange resin (Dowex WX2-200) for about 20 min. long shaken.
  • the loaded ion exchanger is washed three times with 30 ml of methanol, then with water, again with methanol, with dichloromethane and finally again with methanol.
  • the product is eluted with methanol / triethylamine 95: 5.
  • the solvent is removed on the rotary evaporator under reduced pressure. 181 mg (98% of theory) of the title compound are isolated.
  • Example 44 The experiment is carried out in the same manner and dimension as for the compound from Example 42, but using S-3-aminoquinuclidine dihydrochloride. 224 mg (69% of theory) of the title compound are isolated. The analytical data correspond to those of the enantiomeric compound from Example 42.
  • Example 44
  • N, N-diisopropylethylamine and 50 ml DMF are reacted according to the general working procedure (variant B).
  • the crude product is taken up in methanol and together with acidic ion exchange resin (Dowex WX2-200) for about 20 min. long shaken.
  • the loaded ion exchanger is washed successively with methanol, dichloromethane and again with methanol.

Abstract

Nouveaux amides d'acide 2-hétéroarylcarboxylique, procédé de préparation desdits amides et leur utilisation pour la fabrication de médicaments destinés au traitement ou à la prophylaxie de maladies et à l'amélioration de la perception, de la capacité de concentration, de la capacité d'apprentissage et / ou de la mémoire.
PCT/EP2002/014288 2001-12-27 2002-12-16 Amides d'acide 2-heteroarylcarboxylique WO2003055878A1 (fr)

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CA2471593A CA2471593C (fr) 2001-12-27 2002-12-16 2-heteroarylcarboxamides
DE50209614T DE50209614D1 (en) 2001-12-27 2002-12-16 2-heteroarylcarbonsäureamide
US10/500,096 US7732477B2 (en) 2001-12-27 2002-12-16 2-heteroarylcarboxylic acid amides
AU2002358718A AU2002358718A1 (en) 2001-12-27 2002-12-16 2-heteroarylcarboxylic acid amides
EP02793023A EP1461335B1 (fr) 2001-12-27 2002-12-16 Amides d'acide 2-heteroarylcarboxylique
US12/777,764 US8076355B2 (en) 2001-12-27 2010-05-11 2-heteroarylcarboxylic acid amides
US13/289,346 US8884017B2 (en) 2001-12-27 2011-11-04 2-heteroarylcarboxylic acid amides

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DE10164139A DE10164139A1 (de) 2001-12-27 2001-12-27 2-Heteroarylcarbonsäureamide
DE10164139.7 2001-12-27

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Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003104227A1 (fr) * 2002-01-20 2003-12-18 Bayer Healthcare Ag 2-heteroarylcarboxamides
WO2004013136A1 (fr) * 2002-07-29 2004-02-12 Bayer Healthcare Ag Urees de benzothiophene, de benzofuranne et d'indole et utilisation de ces urees comme agonistes des achr alpha 7
US6858613B2 (en) 2002-02-19 2005-02-22 Pfizer Inc. Fused bicyclic-N-bridged-heteroaromatic carboxamides for the treatment of disease
US6894042B2 (en) 2002-02-19 2005-05-17 Pharmacia & Upjohn Company Azabicyclic compounds for the treatment of disease
US6911543B2 (en) 2001-10-02 2005-06-28 Pfizer Inc. Azabicyclic-substituted fused-heteroaryl compounds for the treatment of disease
US7067515B2 (en) 2001-06-12 2006-06-27 Pfizer Inc. Quinuclidines-substituted-multi-cyclic-heteroaryls for the treatment of disease
WO2006098962A1 (fr) * 2005-03-09 2006-09-21 Schering Corporation Composes inhibant l'activite de la kinesine ksp
US7608643B2 (en) 2005-03-09 2009-10-27 Schering Corporation Compounds for inhibiting KSP kinesin activity
WO2010059844A1 (fr) * 2008-11-19 2010-05-27 Envivo Pharmaceuticals, Inc. Traitement de troubles cognitifs par la (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophène-2-carboxamide et les sels de qualité pharmaceutique de celle-ci
US7750022B2 (en) 2003-08-13 2010-07-06 Neurosearch A/S Quinuclidine derivatives and their pharmaceutical use
WO2010132423A1 (fr) 2009-05-11 2010-11-18 Envivo Pharmaceuticals, Inc. Traitement de troubles cognitifs avec certains récepteurs nicotiniques de type alpha-7 à en combinaison avec des inhibiteurs de l'acétylcholinestérase
WO2011146511A1 (fr) 2010-05-17 2011-11-24 Envivo Pharmaceuticals, Inc. Forme cristalline de monohydrate d'hydrochlorure de (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
WO2012101060A1 (fr) 2011-01-27 2012-08-02 Novartis Ag Utilisation d'activateurs du récepteur nicotinique de l'acétylcholine alpha 7
WO2012124825A1 (fr) 2011-03-16 2012-09-20 Mitsubishi Tanabe Pharma Corporation Composés sulfonamides ayant une activité d'antagoniste de trpm8
WO2012127393A1 (fr) 2011-03-18 2012-09-27 Novartis Ag Combinaisons d'activateurs des récepteurs nicotiniques à l'acétylcholine alpha 7 et d'antagonistes des mglur5 destinées à être utilisées dans la dyskinésie induite par la dopamine dans la maladie de parkinson
WO2013002365A1 (fr) 2011-06-30 2013-01-03 東レ株式会社 Agent antiprurigineux
WO2013057687A2 (fr) 2011-10-20 2013-04-25 Novartis Ag Biomarqueurs prédictifs de la sensibilité au traitement par l'activateur du récepteur de l'acétylcholine nicotinique alpha 7
CN103159749A (zh) * 2011-12-13 2013-06-19 南京友杰医药科技有限公司 抗抑郁药维拉佐酮（vilazodone）的合成方法
EP2706854A1 (fr) * 2011-05-09 2014-03-19 Envivo Pharmaceuticals, Inc. Traitement de troubles cognitifs par certains agonistes du récepteur nicotinique alpha-7 en combinaison avec la nicotine
WO2014091388A2 (fr) 2012-12-11 2014-06-19 Novartis Ag Biomarqueur de prédiction de la sensibilité à un traitement par un activateur du récepteur alpha 7 nicotinique de l'acétylcholine
WO2014111751A1 (fr) 2013-01-15 2014-07-24 Novartis Ag Utilisation d'agonistes du récepteur nicotinique alpha 7 pour le traitement de la narcolepsie
WO2014111837A1 (fr) 2013-01-15 2014-07-24 Novartis Ag Utilisation d'agonistes des récepteurs nicotiniques de l'acétylcholine alpha 7
WO2014111838A1 (fr) 2013-01-15 2014-07-24 Novartis Ag Utilisation d'agonistes du récepteur nicotinique alpha 7 de l'acétylcholine
US8884017B2 (en) 2001-12-27 2014-11-11 Bayer Intellectual Property Gmbh 2-heteroarylcarboxylic acid amides
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
EP3153513A1 (fr) 2015-10-06 2017-04-12 Sandoz Ag Encenicline hydrochlorique crystallin
WO2017060287A1 (fr) 2015-10-05 2017-04-13 Sandoz Ag Procédé pour la préparation d'encenicline à partir de chlorure d'acide 7-chloro-benzo[b]thiophène-2-carboxylique et de (r)-quinuclidin-3-amine en présence d'imidazole
WO2017060290A1 (fr) 2015-10-06 2017-04-13 Sandoz Ag Chlorhydrate d'encenicline cristallin
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US9737533B2 (en) 2009-05-12 2017-08-22 Janssen Pharmaceuticals. Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
WO2018011611A1 (fr) * 2016-07-14 2018-01-18 Egis Gyógyszergyár Zrt. Sels pour la production de préparations pharmaceutiques
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
EP3623371A1 (fr) 2014-12-16 2020-03-18 Axovant Sciences GmbH Composés amide de quinuclidine à substituants géminal en tant qu'agonistes des récepteurs nicotiniques de l'acétylcholine 7
US11071729B2 (en) 2007-09-14 2021-07-27 Addex Pharmaceuticals S.A. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR059898A1 (es) 2006-03-15 2008-05-07 Janssen Pharmaceutica Nv Derivados de 3-ciano-piridona 1,4-disustituida y su uso como moduladores alostericos de los receptores mglur2
TW200845978A (en) 2007-03-07 2008-12-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
RU2510396C2 (ru) 2008-09-02 2014-03-27 Янссен Фармасьютикалз, Инк. 3-азабицикло[3.1.0]гексильные производные в качестве модуляторов метаботропных глутаматных рецепторов
AU2015261559A1 (en) * 2008-11-19 2015-12-10 Envivo Pharmaceuticals, Inc. Treatment of cognitive disorders with (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof
AU2009319387B2 (en) 2008-11-28 2012-05-10 Addex Pharma S.A. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
JP5707390B2 (ja) 2009-05-12 2015-04-30 ジャンセン ファーマシューティカルズ， インコーポレイテッド １，２，４−トリアゾロ［４，３−ａ］ピリジン誘導体およびｍＧｌｕＲ２受容体の正のアロステリック調節因子としてのその使用
MY153913A (en) 2009-05-12 2015-04-15 Janssen Pharmaceuticals Inc 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
EP2661435B1 (fr) 2010-11-08 2015-08-19 Janssen Pharmaceuticals, Inc. Dérivés 1,2,4-triazolo[4,3-a]pyridine et leur utilisation en tant que modulateurs allostériques positifs des récepteurs mglur2
EP2643320B1 (fr) 2010-11-08 2015-03-04 Janssen Pharmaceuticals, Inc. Dérivés de la 1,2,4-triazolo [4,3-a] pyridine et leur utilisation en tant que modulateurs allostériques positifs des récepteurs mglur2
EP2649069B1 (fr) 2010-11-08 2015-08-26 Janssen Pharmaceuticals, Inc. Dérivés de 1,2,4-triazolo[4,3-a]pyridine et leur utilisation en tant que modulateurs allostériques positifs des récepteurs mglur2
US20130231365A1 (en) * 2010-11-18 2013-09-05 Gerhard Koenig Treatment of Inflammation with Certain Alpha-7 Nicotinic Acid Receptor Agonists in Combination with Acetylcholinesterase Inhibitors
JP5929483B2 (ja) * 2011-05-10 2016-06-08 住友化学株式会社 植物の生長を促進する方法
JP5929482B2 (ja) * 2011-05-10 2016-06-08 住友化学株式会社 植物の生長を促進する方法
MX2014000146A (es) * 2011-07-01 2014-02-19 Envivo Pharmaceuticals Inc Metodos de tratamiento del deterioro cognitivo limitado.
MX358512B (es) 2012-05-08 2018-08-24 Forum Pharmaceuticals Inc Uso de (r)-7cloro-n-(quinuclidin-3-il) benzo[b] tiofeno-2-carboxamida o una sal farmacéuticamente aceptable de la misma para preparar una composición farmacéutica en el tratamiento de una disfunción cognitiva.
US20130317054A1 (en) 2012-05-24 2013-11-28 Abbvie Inc. Neuronal nicotinic agonist and methods of use
US20130317055A1 (en) 2012-05-24 2013-11-28 Abbvie Inc. Neuronal nicotinic agonist and methods of use
CN105601629A (zh) * 2015-02-02 2016-05-25 苏州晶云药物科技有限公司 (R)-7-氯-N-(奎宁环-3-基)苯并[b]噻吩-2-甲酰胺的盐酸盐的新晶型
WO2016191366A1 (fr) * 2015-05-28 2016-12-01 The Scripps Research Institute Modulateurs pour les sous-unités α2 et α4 de récepteur nicotinique de l'acétylcholine
CN108727416B (zh) * 2017-04-20 2021-03-09 北京大学 三环杂芳香体系酰胺衍生物及其制备和用途

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4605652A (en) * 1985-02-04 1986-08-12 A. H. Robins Company, Inc. Method of enhancing memory or correcting memory deficiency with arylamido (and arylthioamido)-azabicycloalkanes
EP0512350A2 (fr) * 1991-05-10 1992-11-11 MERCK PATENT GmbH Dérivés de l'indole
WO1996033186A1 (fr) * 1995-04-18 1996-10-24 Pharmacia & Upjohn S.P.A. Derives de dihydrobenzofurane substitues utilises en tant qu'agonistes de 5-ht¿4?
US5599937A (en) * 1992-05-11 1997-02-04 Pharmacia Ab Heteroaromatic quinuclidinenes, their use and preparation
JP2002030084A (ja) * 2000-07-18 2002-01-29 Mitsubishi Pharma Corp １−アザビシクロアルカン化合物およびその医薬用途
WO2002100857A1 (fr) * 2001-06-12 2002-12-19 Pharmacia & Upjohn Company Multi-heteroaryles cycliques substitues par quinuclidines pour le traitement de maladies

Family Cites Families (180)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5122528A (en) 1983-12-22 1992-06-16 Erbamont, Inc. Analgesic use of benzobicyclic carboxamides
DE201165T1 (de) 1985-03-14 1989-04-20 Beecham Group P.L.C., Brentford, Gb Arzneimittel zur behandlung von emesis, anxietas und "irritable bowel syndrome".
HU202108B (en) 1986-07-30 1991-02-28 Sandoz Ag Process for producing pharmaceutical compositions containing serotonine antqgonistic derivatives of indol-carboxylic acid or imidazolyl-methyl-carbazol
DE3827253A1 (de) 1987-08-20 1989-03-02 Sandoz Ag Ester und amide von cyclischen carbonsaeuren und cyclischen alkoholen und aminen sowie verfahren zu deren herstellung und sie enthaltende therapeutische zusammensetzungen
DE3740984A1 (de) 1987-12-03 1989-06-15 Sandoz Ag N-oxide von heterocyclischen carbonsaeurederivaten bzw. verfahren zu deren herstellung und deren verwendung
US5198437A (en) 1987-12-10 1993-03-30 Duphar International Research B.V. 1,7-annelated indolecarboxylic acid esters and amides
DK680788A (da) 1987-12-10 1989-06-11 Duphar Int Res Indolcarboxylsyreestere og -amider, deres fremstilling of laegemidler indeholdende forbindelserne
US4863919A (en) 1988-02-01 1989-09-05 A. H. Robins Company, Incorporated Method of enhancing memory or correcting memory deficiency with arylamido(and arylthiomido)-azabicycloalkanes
DE3810552A1 (de) 1988-03-29 1989-10-19 Sandoz Ag Ester und amide von indol-, benzo(b)thiopen-, benzo(b)furancarbonsaeuren oder 4-amino-2-methoxy-benzolsaeuren mit n-heterocyclischen oder n-heterobicyclischen alkoholen oder aminen, verfahren zu deren herstellung sie enthaltende pharmazeutische zusammensetzungen sowie applikator zur verabreichung derselben
EP0353371A1 (fr) 1988-08-04 1990-02-07 Synthelabo R-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides et thiobenzamides améliorant la mémoire
IE62662B1 (en) 1989-01-06 1995-02-22 Elan Corp Plc Use of nicotine in the treatment of conditions susceptible to said treatment
GB8928837D0 (en) 1989-12-21 1990-02-28 Beecham Group Plc Pharmaceuticals
US5189041A (en) 1990-11-16 1993-02-23 Syntex (U.S.A.) Inc. Tricyclic 5-ht3 receptor antagonists
GB9201749D0 (en) 1992-01-28 1992-03-11 Smithkline Beecham Plc Medicaments
JP2699794B2 (ja) * 1992-03-12 1998-01-19 三菱化学株式会社 チエノ〔３，２−ｂ〕ピリジン誘導体
US5977144A (en) 1992-08-31 1999-11-02 University Of Florida Methods of use and compositions for benzylidene- and cinnamylidene-anabaseines
HUT77352A (hu) 1994-08-24 1998-03-30 Astra Aktiebolag Spiro[aza-bicikloalkán-oxazolidin]-2'-on-származékok, eljárás előállításukra és az ezeket tartalmazó gyógyszerkészítmények
US5863936A (en) 1995-04-18 1999-01-26 Geron Corporation Telomerase inhibitors
US5703116A (en) 1995-04-18 1997-12-30 Geron Corporation Telomerase Inhibitors
US5656638A (en) 1995-04-18 1997-08-12 Geron Corporation Telomerase inhibitors
US5760062A (en) 1995-04-18 1998-06-02 Geron Corporation Telomerase inhibitors
GB9606736D0 (en) 1996-02-19 1996-06-05 Shire International Licensing Therapeutic method
SE9600683D0 (sv) 1996-02-23 1996-02-23 Astra Ab Azabicyclic esters of carbamic acids useful in therapy
FR2756826B1 (fr) 1996-12-05 1999-01-08 Adir Nouveaux derives tetrahydropyridiniques substitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
JP4447663B2 (ja) 1997-05-30 2010-04-07 ニューロサーチ、アクティーゼルスカブ ニコチン性ａｃｈレセプターに於けるコリン作動性リガンドとしての８−アザビシクロ（３．２．１）オクト−２−エン及びオクタン誘導体
US7214686B2 (en) 1997-06-30 2007-05-08 Targacept, Inc. Pharmaceutical compositions and methods for effecting dopamine release
AR013184A1 (es) 1997-07-18 2000-12-13 Astrazeneca Ab Aminas heterociclicas espiroazobiciclicas, composicion farmaceutica, uso de dichas aminas para preparar medicamentos y metodo de tratamiento o profilaxis
JPH1180027A (ja) 1997-09-12 1999-03-23 Dai Ichi Seiyaku Co Ltd 向知性薬
US6875606B1 (en) 1997-10-23 2005-04-05 The United States Of America As Represented By The Department Of Veterans Affairs Human α-7 nicotinic receptor promoter
GB9804343D0 (en) 1998-02-27 1998-04-22 Univ Cardiff Chemical compounds
US6277870B1 (en) 1998-05-04 2001-08-21 Astra Ab Use
ATE255888T1 (de) 1998-06-01 2003-12-15 Ortho Mcneil Pharm Inc Tetrahydronaphtalene verbindungen und deren verwendung zur behandlung von neurodegenerativen krankheiten
CA2341989A1 (fr) 1998-08-25 2000-03-02 Ortho-Mcneil Pharmaceutical, Inc. Pyridyl ethers et thioethers tenant lieu de ligands pour le recepteur de l'acetycholine nicotinique, et application therapeutique
CA2343320A1 (fr) 1998-09-18 2000-03-30 The Rockefeller University Lynx, une nouvelle famille de ligands recepteurs dans le systeme nerveux central, acides nucleiques et proteines correspondants et leurs utilisations
US6953855B2 (en) 1998-12-11 2005-10-11 Targacept, Inc. 3-substituted-2(arylalkyl)-1-azabicycloalkanes and methods of use thereof
US6432975B1 (en) 1998-12-11 2002-08-13 Targacept, Inc. Pharmaceutical compositions and methods for use
SE9900100D0 (sv) 1999-01-15 1999-01-15 Astra Ab New compounds
FR2790474B1 (fr) 1999-03-05 2001-04-06 Synthelabo Derives de pyridopyranoazepines, leur preparation et leur application en therapeutique
FR2791678B1 (fr) 1999-03-30 2001-05-04 Synthelabo Derives de 1,4-diazabicyclo [3.2.2] nonane-4-carboxylates et -carboxamides, leur preparation et leur application en therapeutique
SE9903760D0 (sv) 1999-10-18 1999-10-18 Astra Ab New compounds
SE9903996D0 (sv) 1999-11-03 1999-11-03 Astra Ab New compounds
SE9903998D0 (sv) 1999-11-03 1999-11-03 Astra Ab New compounds
SE9903997D0 (sv) 1999-11-03 1999-11-03 Astra Ab New compounds
US6416735B1 (en) 1999-11-08 2002-07-09 Research Triangle Institute Ligands for α-7 nicotinic acetylcholine receptors based on methyllcaconitine
SE9904176D0 (sv) 1999-11-18 1999-11-18 Astra Ab New use
WO2001040261A1 (fr) 1999-12-01 2001-06-07 Ortho-Mcneil Pharmaceutical, Inc. Procede de diagnostic de maladies neurodegeneratives
CA2393538A1 (fr) 1999-12-14 2001-06-21 Pharmacia & Upjohn Company Canaux ioniques humains
FR2804430B1 (fr) 2000-01-28 2002-03-22 Sanofi Synthelabo Derives de 4-heteroaryl-1,4-diazabicyclo[3.2.2] nonane, leur preparation et leur application en therapeutique
SE0000540D0 (sv) 2000-02-18 2000-02-18 Astrazeneca Ab New compounds
IT1314572B1 (it) 2000-02-23 2002-12-20 Perini Fabio Spa Dispositivo per eliminare i rifili di testa e di coda da serie dirotoli e per smistare i rotoli
WO2001066546A1 (fr) 2000-03-09 2001-09-13 Mitsubishi Pharma Corporation Composes spiro, leur procede de preparation et leur utilisation comme medicaments
GB0010955D0 (en) 2000-05-05 2000-06-28 Novartis Ag Organic compounds
EP1287001B1 (fr) 2000-06-06 2004-09-29 Pfizer Products Inc. Derives de thiophene utilises comme agents anticancereux
TW593223B (en) 2000-06-20 2004-06-21 Merz Pharma Gmbh & Co Kgaa 1-amino-alkylcyclohexanes as 5-HT3 and neuronal nicotinic receptor antagonists
FR2810664B1 (fr) 2000-06-27 2004-12-24 Adir Nouveaux composes cyclopropaniques 1,1 et 1,2-dissubstitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US20030092613A1 (en) 2000-08-14 2003-05-15 Lee Daniel H. S. Alpha7 nicotinic receptor peptides as ligands for beta amyloid peptides
US6492385B2 (en) 2000-08-18 2002-12-10 Pharmacia & Upjohn Company Quinuclidine-substituted heteroaryl moieties for treatment of disease
AU2001282874A1 (en) 2000-08-18 2002-03-04 Pharmacia And Upjohn Company Quinuclidine-substituted aryl moieties for treatment of disease (nicotinic acetylcholine receptor ligands)
US6486172B2 (en) 2000-08-18 2002-11-26 Pharmacia & Upjohn Company Quinuclidine-substituted aryl compounds for treatment of disease
US6492386B2 (en) 2000-08-18 2002-12-10 Pharmacia & Upjohn Company Quinuclidine-substituted aryl compounds for treatment of disease
WO2002015662A2 (fr) 2000-08-21 2002-02-28 Pharmacia & Upjohn Company Fractions heteroaryle substituees par quinuclidine destinees au traitement de maladies
AU2001282875A1 (en) 2000-08-21 2002-03-04 Pharmacia And Upjohn Company Quinuclidine-substituted heteroaryl moieties for treatment of disease
GB0021885D0 (en) 2000-09-06 2000-10-18 Fujisawa Pharmaceutical Co New use
DE10044905A1 (de) 2000-09-12 2002-03-21 Merck Patent Gmbh (2-Azabicyclo[2.2.1]hept-7-yl)methanol-Derivate als nikontinische Acetylcholinrezeptor Agonisten
ATE385497T1 (de) 2000-12-01 2008-02-15 Neurosearch As 3-substituierte quinuclidin-derivate und deren verwendung als nikotinischen agonisten
US20020086871A1 (en) 2000-12-29 2002-07-04 O'neill Brian Thomas Pharmaceutical composition for the treatment of CNS and other disorders
WO2002057275A1 (fr) 2001-01-17 2002-07-25 University Of Kentucky Research Foundation Analogues de nicotine contenant du bore utilises dans le traitement des pathologies liees au systeme nerveux central
DE60216830T2 (de) 2001-02-06 2007-06-14 Pfizer Products Inc., Groton Pharmazeutische Zusammensetzungen zur Behandlung von Störungen des ZNS oder anderen Erkrankungen
GB0108337D0 (en) 2001-04-03 2001-05-23 Novartis Ag Organic compounds
PE20021019A1 (es) 2001-04-19 2002-11-13 Upjohn Co Grupos azabiciclicos sustituidos
US6569865B2 (en) 2001-06-01 2003-05-27 Astrazeneca Ab Spiro 1-azabicyclo[2.2.2]octane-3,2′(3′h)-furo[2,3-b]pyridine
CN1294136C (zh) 2001-06-01 2007-01-10 阿斯特拉曾尼卡有限公司 用于治疗的烟碱乙酰胆碱受体新型配体
AR036041A1 (es) 2001-06-12 2004-08-04 Upjohn Co Compuestos aromaticos heterociclicos sustituidos con quinuclidina y composiciones farmaceuticas que los contienen
US6562816B2 (en) 2001-08-24 2003-05-13 Pharmacia & Upjohn Company Substituted-heteroaryl-7-aza[2.2.1]bicycloheptanes for the treatment of disease
JP2003081978A (ja) 2001-09-10 2003-03-19 Mitsubishi Pharma Corp スピロ環式化合物およびその医薬用途
CA2460075A1 (fr) 2001-09-12 2003-03-20 Donn Gregory Wishka 7-aza`2.2.1!bicycloheptanes substitues pour traitement de maladies
BR0213612A (pt) 2001-10-02 2004-08-24 Upjohn Co Composto, composição farmacêutica, uso do composto e método para tratamento de doença ou condição
JP2005511574A (ja) 2001-10-26 2005-04-28 ファルマシア アンド アップジョン カンパニー リミティド ライアビリティー カンパニー Ｎａｃｈｒアゴニストとしてのｎ−アザビシクロ−置換ヘテロ二環式カルボキサミド
JP2005511613A (ja) 2001-11-08 2005-04-28 ファルマシア アンド アップジョン カンパニー リミティド ライアビリティー カンパニー 疾患治療用アザビシクロ置換ヘテロアリール化合物
EP1442037A1 (fr) 2001-11-09 2004-08-04 PHARMACIA & UPJOHN COMPANY Composes heterocycliques fusionnes avec un groupe phenyl-azabicyclique et leur utilisation en tant que ligands de recepteur nachr alpha 7
GB0127008D0 (en) 2001-11-09 2002-01-02 Novartis Ag Organic compounds
DE10156719A1 (de) 2001-11-19 2003-05-28 Bayer Ag Heteroarylcarbonsäureamide
FR2832713B1 (fr) 2001-11-23 2004-02-13 Sanofi Synthelabo Derives de 4-(1,3,4-thiadiazol-2-yl)-1,4-diazabicyclo[3.2.2] nonane, leur preparation et leur application en therapeutique
FR2832712B1 (fr) 2001-11-23 2004-02-13 Sanofi Synthelabo Derives de 4-(oxadiazol-3-yl)-1,4-diazabicyclo[3.2.2]nonane, leur preparation et leur application en therapeutique
FR2832714B1 (fr) 2001-11-23 2004-07-16 Sanofi Synthelabo Derives de 4-(oxazolopyridin-2-yl)-1,4-diazabicyclo[3.2.2] nonane, leur preparation et leur application en therapeutique
PL374384A1 (en) 2001-12-14 2005-10-17 Targacept, Inc. Methods and compositions for treatment of central nervous system disorders
DE10162442A1 (de) 2001-12-19 2003-07-03 Bayer Ag Monocyclische N-Aryl-amide
DE10162375A1 (de) 2001-12-19 2003-07-10 Bayer Ag Bicyclische N-Aryl-amide
DE10164139A1 (de) 2001-12-27 2003-07-10 Bayer Ag 2-Heteroarylcarbonsäureamide
WO2003104227A1 (fr) 2002-01-20 2003-12-18 Bayer Healthcare Ag 2-heteroarylcarboxamides
BR0307714A (pt) 2002-02-15 2005-02-09 Upjohn Co Benzoilamidas substituìdas com azabiciclo e tioamidas para tratamento de distúrbios relacionados ao cns
AU2003217275A1 (en) 2002-02-19 2003-09-09 Pharmacia And Upjohn Company Azabicyclic compounds for the treatment of disease
CA2476681A1 (fr) 2002-02-19 2003-08-28 Bruce N. Rogers Carboxamides hetero-aromatiques n-pontes bicycliques condenses destines au traitement de maladies
AU2003214936A1 (en) 2002-02-20 2003-09-09 Pharmacia And Upjohn Company Azabicyclic compounds with alfa7 nicotinic acetylcholine receptor activity
DE10211416A1 (de) 2002-03-15 2003-09-25 Bayer Ag Essig- und Propionsäureamide
DE10211415A1 (de) 2002-03-15 2003-09-25 Bayer Ag Bicyclische N-Biarylamide
CA2482311C (fr) 2002-04-18 2009-12-08 Astrazeneca Ab Composes furyle
DE60328010D1 (de) 2002-04-18 2009-07-30 Astrazeneca Ab Heterocyclische verbindungen
JP4511196B2 (ja) 2002-04-18 2010-07-28 アストラゼネカ・アクチエボラーグ チエニル化合物
AU2003234203A1 (en) 2002-04-24 2003-11-10 Memory Pharmaceuticals Corporation Method for assay of cognition and memory based on low frequency stimulation
US20030236287A1 (en) 2002-05-03 2003-12-25 Piotrowski David W. Positive allosteric modulators of the nicotinic acetylcholine receptor
JP2005524713A (ja) 2002-05-07 2005-08-18 ニューロサーチ、アクティーゼルスカブ 新規ジアザビシクロビアリール誘導体
JP2005524712A (ja) 2002-05-07 2005-08-18 ニューロサーチ、アクティーゼルスカブ 新規アザシクロエチニル誘導体
EP1502110A4 (fr) 2002-05-09 2007-09-05 Memory Pharm Corp Cellules qm-7 et qt-6 transfectees avec des recepteurs mutants a canal a expression de surface et tests faisant appel a ces cellules transfectees
CA2495432A1 (fr) 2002-07-17 2004-01-22 Warner-Lambert Company Llc Combinaison d'un inhibiteur carboxylique allosterique de metalloproteinase-13 de matrice et de celecoxibe ou de valdecoxibe
DE10234424A1 (de) 2002-07-29 2004-02-12 Bayer Ag Benzothiophen-, Benzofuran- und Indolharnstoffe
WO2004013137A1 (fr) 2002-08-01 2004-02-12 Pharmacia & Upjohn Company Llc Composes azabicyclique de 1h-pyrazole et 1h-pyrrole servant a effectuer un traitement therapeutique
WO2004014377A1 (fr) 2002-08-13 2004-02-19 Warner-Lambert Company Llc Derives de 4-hydroxyquinoleine utilises comme inhibiteurs de metalloproteases matricielles
RU2323217C2 (ru) 2002-08-14 2008-04-27 Ньюросерч А/С Новые хинуклидиновые производные и их применение
SE0202430D0 (sv) 2002-08-14 2002-08-14 Astrazeneca Ab New Compounds
SE0202465D0 (sv) 2002-08-14 2002-08-14 Astrazeneca Ab New compounds
SE0202598D0 (sv) 2002-09-02 2002-09-02 Astrazeneca Ab Alpha-7 Nicotinic receptor agonists and statins in combination
GB0220581D0 (en) 2002-09-04 2002-10-09 Novartis Ag Organic Compound
RU2391341C2 (ru) 2002-09-25 2010-06-10 Мемори Фармасьютиклз Корпорейшн Индазолы, бензотиазолы, бензоизотиазолы, их получение и применение
WO2004039321A2 (fr) 2002-10-29 2004-05-13 Miicro, Inc. Therapie associee agoniste nicotinique/agoniste d1 pour le traitement de la maladie d'alzheimer
AU2003269401A1 (en) 2002-11-01 2004-05-25 Pharmacia & Upjohn Company Llc Compounds having both alpha7 nachr agonist and 5ht antagonist activity for treatment of cns diseases
DE60309740T2 (de) 2002-11-11 2007-03-29 Neurosearch A/S 1,4-dizabicyclo(3,2,2)nonane derivative, verfahren zu ihrer herstellung und therapeutical verwendung
WO2004052889A1 (fr) 2002-12-06 2004-06-24 Pharmacia & Upjohn Company Llc Composes utilises comme ligands radioactifs pour diagnostiquer une maladie
WO2004052894A1 (fr) 2002-12-06 2004-06-24 Pharmacia & Upjohn Company Llc Sels fumarates cristallins de furo[2,3-c]pyridinyle carboxamide a substitution 1-azabicyclo [2.2.2]oct et compositions et preparations contenant lesdits sels
EP1572205A2 (fr) 2002-12-11 2005-09-14 Pharmacia & Upjohn Company LLC Traitement de maladies a l'aide de combinaisons d'agonistes du recepteur nicotinique de l'acetylcholine alpha 7 et d'autres composes
EA200500783A1 (ru) 2002-12-11 2005-12-29 ФАРМАЦИЯ ЭНД АПДЖОН КОМПАНИ ЭлЭлСи Комбинация для лечения синдрома дефицита внимания с гиперактивностью
WO2004056744A1 (fr) 2002-12-23 2004-07-08 Janssen Pharmaceutica N.V. Adamantyl acetamides utilises comme inhibiteurs de la hydroxysteroide deshydrogenase
US20050031651A1 (en) 2002-12-24 2005-02-10 Francine Gervais Therapeutic formulations for the treatment of beta-amyloid related diseases
MXPA05007689A (es) 2003-01-22 2005-09-30 Pharmacia & Upjohn Co Llc Tratamiento de enfermedades con agonistas completos del receptor alfa-7 de nach.
MXPA05010496A (es) 2003-03-28 2005-11-16 Pharmacia & Upjohn Co Llc Moduladores alostericos positivos del receptor de acetilcolina nicotinico.
DE10334724A1 (de) 2003-07-30 2005-02-24 Bayer Healthcare Ag N-Biarylamide
US20050119249A1 (en) 2003-12-02 2005-06-02 Erik Buntinx Method of treating neurodegenerative diseases using D4 and 5-HT2A antagonists, inverse agonists or partial agonists
US20050245531A1 (en) 2003-12-22 2005-11-03 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
NZ550534A (en) 2004-03-25 2009-07-31 Memory Pharm Corp Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, and preparation and uses thereof
GB0412467D0 (en) 2004-06-04 2004-07-07 Astrazeneca Ab Chemical compounds
EP1776106B1 (fr) 2004-06-22 2013-08-07 Vertex Pharmaceuticals Incorporated Dérivés hétérocycliques pour moduler les canaux calciques
GB0420719D0 (en) 2004-09-17 2004-10-20 Addex Pharmaceuticals Sa Novel allosteric modulators
JP2008523058A (ja) 2004-12-10 2008-07-03 アボット・ラボラトリーズ 縮合ビシクロ複素環置換キヌクリジン誘導体
EP1838690A2 (fr) 2004-12-21 2007-10-03 Devgen N.V. Composés avec une activité pour les canaux ioniques kv4
JP2009509964A (ja) 2005-09-23 2009-03-12 メモリー・ファーマシューティカルズ・コーポレイション インダゾール類、ベンゾチアゾール類、ベンゾイソオキサゾール類、ピラゾロピリジン類、イソチアゾロピリジン類、およびそれらの製造と用途
US8148391B2 (en) 2006-10-23 2012-04-03 Cephalon, Inc. Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors
WO2008051599A2 (fr) 2006-10-27 2008-05-02 Medivation Neurology, Inc. Procédés et combinaison de thérapies pour le traitement de la maladie d'alzheimer
MX2009008439A (es) 2007-02-12 2009-08-13 Intermune Inc Nuevos inhibidores de la replicacion del virus de hepatitis c.
NZ580904A (en) 2007-05-11 2012-02-24 Pfizer Amino-heterocyclic compounds for inhibiting pde9
SA08290475B1 (ar) 2007-08-02 2013-06-22 Targacept Inc (2s، 3r)-n-(2-((3-بيردينيل)ميثيل)-1-آزا بيسيكلو[2، 2، 2]أوكت-3-يل)بنزو فيوران-2-كربوكساميد، وصور أملاحه الجديدة وطرق استخدامه
MX2010002098A (es) 2007-08-31 2010-03-30 Eisai R&D Man Co Ltd Compuesto policiclico.
US7935815B2 (en) 2007-08-31 2011-05-03 Eisai R&D Management Co., Ltd. Imidazoyl pyridine compounds and salts thereof
WO2009046025A1 (fr) 2007-10-01 2009-04-09 Comentis, Inc. Dérivés de quinuclidine substitué en position 4, procédés de production et utilisations pharmaceutiques de ceux-ci
NZ585055A (en) 2007-11-21 2012-07-27 Abbott Lab Biaryl substituted azabicyclic alkane derivatives as nicotinic acetylcholine receptor activity modulators
WO2009073788A1 (fr) 2007-12-07 2009-06-11 Firestone Leigh H Compositions et procédés pour traiter des femmes ménopausées
NZ589304A (en) 2008-04-29 2012-03-30 Pharnext Combination compositions for treating alzheimer disease and related disorders with zonisamide and acamprosate
CN102065897B (zh) 2008-04-29 2013-11-13 法奈科斯公司 基于磺胺异噁唑的组合物用于制备治疗阿茨海默病的药物的应用
DK2282778T3 (en) 2008-04-29 2017-05-01 Pharnext NEW THERAPEUTIC APPROACHES TO TREAT ALZHEIMER'S DISEASE AND RELATED DISEASES THROUGH A MODULATION OF ANGIOGENIC
BRPI0920927A2 (pt) 2008-11-13 2019-09-24 Link Medicine Corp derivados de azaquinolinona e usos dos mesmos
TR201807944T4 (tr) 2008-11-19 2018-06-21 Forum Pharmaceuticals Inc (R)-7-kloro-N-(kinüklidin-3-il)benzo[b]tiyofen-2-karboksamit ve bunun farmasötik olarak kabul edilebilir tuzları ile şizofreninin negatif belirtilerinin tedavisi.
US8674095B2 (en) 2008-12-19 2014-03-18 Afraxis Holdings, Inc. Compounds for treating neuropsychiatric conditions
EP2381955A4 (fr) 2008-12-30 2013-01-16 Univ Ramot Polythérapies utilisant le nap
TWI404721B (zh) 2009-01-26 2013-08-11 Pfizer 胺基－雜環化合物
WO2010095940A2 (fr) 2009-02-20 2010-08-26 To-Bbb Holding B.V. Sustème d'administration de médicament à base de glutathionne
CN102333777B (zh) 2009-02-26 2014-06-25 卫材R&D管理有限公司 含氮的稠合杂环化合物及其作为β淀粉样蛋白生成抑制剂的用途
JP2012051806A (ja) 2009-02-26 2012-03-15 Eisai R & D Management Co Ltd イミダゾリルピラジン誘導体
JP2012051807A (ja) 2009-02-26 2012-03-15 Eisai R & D Management Co Ltd アリールイミダゾール化合物
JP2012523437A (ja) 2009-04-13 2012-10-04 セラヴァンス， インコーポレーテッド 認知障害の治療のための５−ｈｔ４受容体アゴニスト化合物
JP5808319B2 (ja) 2009-05-11 2015-11-10 フォルム ファーマシューティカルズ、インコーポレイテッド アセチルコリンエステラーゼ阻害剤と組み合わせた特定のα７ニコチン酸受容体を用いた認知障害の治療
CA2764387A1 (fr) 2009-06-05 2010-12-09 Link Medicine Corporation Derives d'aminopyrrolidinone et utilisations de ceux-ci
EP2453896A4 (fr) 2009-07-16 2013-01-09 Afraxis Inc Méthodes de traitement de la schizophrénie
JP5636428B2 (ja) 2009-09-17 2014-12-03 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプＪａｎｓｓｅｎ Ｐｈａｒｍａｃｅｕｔｉｃａ Ｎａａｍｌｏｚｅ Ｖｅｎｎｏｏｔｓｃｈａｐ 置換ｎ−フェニル−１−（４−ピリジニル）−１ｈ−ピラゾル−３−アミン類
JO3250B1 (ar) 2009-09-22 2018-09-16 Novartis Ag إستعمال منشطات مستقبل نيكوتينيك أسيتيل كولين ألفا 7
EP2485727A4 (fr) 2009-10-06 2013-05-01 Afraxis Inc Pyrrolopyrazoles pour le traitement de troubles du snc
WO2011044537A2 (fr) 2009-10-09 2011-04-14 Afraxis, Inc. Procédés pour le traitement de la maladie d'alzheimer
US8372970B2 (en) 2009-10-09 2013-02-12 Afraxis, Inc. 8-ethyl-6-(aryl)pyrido[2,3-D]pyrimidin-7(8H)-ones for the treatment of CNS disorders
IN2012DN03312A (fr) 2009-10-22 2015-10-23 Fibrotech Therapeutics Pty Ltd
EP2322163A1 (fr) 2009-11-03 2011-05-18 Pharnext Nouvelles approches thérapeutiques pour traiter la maladie d'Alzheimer
WO2011057199A1 (fr) 2009-11-06 2011-05-12 Adenios, Inc. Compositions destinées à traiter des troubles du snc
WO2011063415A2 (fr) 2009-11-23 2011-05-26 Afraxis, Inc. Méthodes de traitement de trouble cognitif léger
JO3078B1 (ar) 2009-11-27 2017-03-15 Janssen Pharmaceutica Nv مورفولينوثيازولات بصفتها منظمات الوستيرية نوع الفا 7 موجبة
DK2512243T3 (en) 2009-12-17 2016-07-25 Merck Sharp & Dohme POSITIVE ALLOSTERIC QUINOLINAMIDE M1 RECEPTOR MODULATORS
US20110274628A1 (en) 2010-05-07 2011-11-10 Borschke August J Nicotine-containing pharmaceutical compositions
ES2746850T3 (es) 2010-05-17 2020-03-09 Forum Pharmaceuticals Inc Formulaciones farmacéuticas que comprenden formas cristalinas de clorhidrato de (R)-7-cloro-N-(quinuclidin-3-il)benzo(b)tiofeno-2-carboxamida monohidratado
WO2011156640A2 (fr) 2010-06-09 2011-12-15 Afraxis, Inc. 8-(hétéroarylméthyl)pyrido[2,3-d]pyrimidin-7(8h)-ones pour le traitement de troubles du snc
WO2011156646A2 (fr) 2010-06-09 2011-12-15 Afraxis, Inc. 8-(sulfonylaryl)pyrido[2,3-d]pyrimidin-7(8h)-ones pour le traitement de troubles du snc
WO2011156780A2 (fr) 2010-06-10 2011-12-15 Afraxis, Inc. 8-(sulfonylbenzyl)pyrido[2,3-d]pyrimidin-7(8h)-ones pour le traitement de troubles du snc
EP2580215A4 (fr) 2010-06-10 2014-01-15 Afraxis Holdings Inc 8-(hétérocycyl)pyrido[2,3-d]pyrimidin-7(8h)-ones pour le traitement de troubles du snc
US8680099B2 (en) 2010-06-10 2014-03-25 Afraxis Holdings, Inc. 6-(ethynyl)pyrido[2,3-D]pyrimidin-7(8H)-ones for the treatment of CNS disorders
WO2011159945A2 (fr) 2010-06-16 2011-12-22 Afraxis, Inc. Procédés pour traiter des affections neurologiques

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4605652A (en) * 1985-02-04 1986-08-12 A. H. Robins Company, Inc. Method of enhancing memory or correcting memory deficiency with arylamido (and arylthioamido)-azabicycloalkanes
EP0512350A2 (fr) * 1991-05-10 1992-11-11 MERCK PATENT GmbH Dérivés de l'indole
US5599937A (en) * 1992-05-11 1997-02-04 Pharmacia Ab Heteroaromatic quinuclidinenes, their use and preparation
WO1996033186A1 (fr) * 1995-04-18 1996-10-24 Pharmacia & Upjohn S.P.A. Derives de dihydrobenzofurane substitues utilises en tant qu'agonistes de 5-ht¿4?
JP2002030084A (ja) * 2000-07-18 2002-01-29 Mitsubishi Pharma Corp １−アザビシクロアルカン化合物およびその医薬用途
WO2002100857A1 (fr) * 2001-06-12 2002-12-19 Pharmacia & Upjohn Company Multi-heteroaryles cycliques substitues par quinuclidines pour le traitement de maladies

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 2002, no. 05 3 May 2002 (2002-05-03) *

Cited By (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7067515B2 (en) 2001-06-12 2006-06-27 Pfizer Inc. Quinuclidines-substituted-multi-cyclic-heteroaryls for the treatment of disease
US6911543B2 (en) 2001-10-02 2005-06-28 Pfizer Inc. Azabicyclic-substituted fused-heteroaryl compounds for the treatment of disease
US8884017B2 (en) 2001-12-27 2014-11-11 Bayer Intellectual Property Gmbh 2-heteroarylcarboxylic acid amides
WO2003104227A1 (fr) * 2002-01-20 2003-12-18 Bayer Healthcare Ag 2-heteroarylcarboxamides
US6858613B2 (en) 2002-02-19 2005-02-22 Pfizer Inc. Fused bicyclic-N-bridged-heteroaromatic carboxamides for the treatment of disease
US6894042B2 (en) 2002-02-19 2005-05-17 Pharmacia & Upjohn Company Azabicyclic compounds for the treatment of disease
US10214524B2 (en) 2002-06-10 2019-02-26 Bayer Intellectual Property Gmbh 2-heteroaryl carboxamides
US7977485B2 (en) 2002-06-10 2011-07-12 Bayer Schering Pharma Aktiengesellshaft 2-heteroaryl carboxamides
US9067931B2 (en) 2002-06-10 2015-06-30 Bayer Intellectual Property Gmbh 2-heteroaryl carboxamides
US8153799B2 (en) 2002-07-29 2012-04-10 Bayer Schering Pharma Aktiengesellschaft Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists
US7795453B2 (en) 2002-07-29 2010-09-14 Bayer Schering Pharma Aktiengesellschaft Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists
US8772511B2 (en) 2002-07-29 2014-07-08 Bayer Intellectual Property Gmbh Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists
WO2004013136A1 (fr) * 2002-07-29 2004-02-12 Bayer Healthcare Ag Urees de benzothiophene, de benzofuranne et d'indole et utilisation de ces urees comme agonistes des achr alpha 7
US10196388B2 (en) 2002-07-29 2019-02-05 Bayer Intellectual Property Gmbh Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists
US9714242B2 (en) 2002-07-29 2017-07-25 Bayer Intellectual Property Gmbh Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists
US7750022B2 (en) 2003-08-13 2010-07-06 Neurosearch A/S Quinuclidine derivatives and their pharmaceutical use
US7608643B2 (en) 2005-03-09 2009-10-27 Schering Corporation Compounds for inhibiting KSP kinesin activity
JP2008533019A (ja) * 2005-03-09 2008-08-21 シェーリング コーポレイション Ｋｓｐキネシン活性を阻害するための化合物
WO2006098962A1 (fr) * 2005-03-09 2006-09-21 Schering Corporation Composes inhibant l'activite de la kinesine ksp
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US11071729B2 (en) 2007-09-14 2021-07-27 Addex Pharmaceuticals S.A. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
RU2662560C2 (ru) * 2008-11-19 2018-07-26 Форум Фармасьютикалз, Инк. Лечение когнитивных расстройств (r)-7-хлор-n-(хинуклидин-3-ил)бензо[в]тиофен-2-карбосамидом и его фармацевтически приемлемыми солями
EP2540297A1 (fr) 2008-11-19 2013-01-02 Envivo Pharmaceuticals, Inc. Traitement de troubles cognitifs par la (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophène-2-carboxamide et ses sels de qualité pharmaceutique
EP2889033A1 (fr) 2008-11-19 2015-07-01 Forum Pharmaceuticals Inc. Traitement de symptômes négatifs de la schizophrénie avec (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide et leurs sels pharmaceutiquement acceptables
EP3357495A1 (fr) * 2008-11-19 2018-08-08 Forum Pharmaceuticals Inc. Traitement de troubles cognitifs avec (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophène-2-carboxamide et leurs sels pharmaceutiquement acceptables
RU2532327C2 (ru) * 2008-11-19 2014-11-10 Форум Фармастютикалз, Инк. ЛЕЧЕНИЕ КОГНИТИВНЫХ РАССТРОЙСТВ (R)-7-ХЛОР-N-(ХИНУКЛИДИН-3-ИЛ) БЕНЗО[b] ТИОФЕН-2-КАРБОКСАМИДОМ И ЕГО ФАРМАЦЕВТИЧЕСКИ ПРИЕМЛЕМЫМИ СОЛЯМИ
WO2010059844A1 (fr) * 2008-11-19 2010-05-27 Envivo Pharmaceuticals, Inc. Traitement de troubles cognitifs par la (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophène-2-carboxamide et les sels de qualité pharmaceutique de celle-ci
CN102802620A (zh) * 2009-05-11 2012-11-28 英维沃医药有限公司 使用某种α-7烟酸受体与乙酰胆碱酯酶抑制剂结合治疗认知障碍
WO2010132423A1 (fr) 2009-05-11 2010-11-18 Envivo Pharmaceuticals, Inc. Traitement de troubles cognitifs avec certains récepteurs nicotiniques de type alpha-7 à en combinaison avec des inhibiteurs de l'acétylcholinestérase
US9737533B2 (en) 2009-05-12 2017-08-22 Janssen Pharmaceuticals. Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US10071095B2 (en) 2009-05-12 2018-09-11 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of neurological and psychiatric disorders
RU2577334C2 (ru) * 2010-05-17 2016-03-20 Энвиво Фармасьютикалз, Инк. КРИСТАЛЛИЧЕСКАЯ ФОРМА МОНОГИДРАТА ГИДРОХЛОРИДА (R)-7-ХЛОР-N-(ХИНУКЛИДИН-3-ИЛ)БЕНЗО[b]ТИОФЕН-2-КАРБОКСАМИДА
WO2011146511A1 (fr) 2010-05-17 2011-11-24 Envivo Pharmaceuticals, Inc. Forme cristalline de monohydrate d'hydrochlorure de (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide
EP3604302A1 (fr) 2010-05-17 2020-02-05 Forum Pharmaceuticals Inc. Préparation des formes cristallines de (r)-7-chloro-n-(quinuclidin-3-yl) benzo(b)thiophène-2-carboxamide hydrochlorure monohydrate
EP3272748A1 (fr) 2010-05-17 2018-01-24 Forum Pharmaceuticals Inc. Formulations pharmaceutiques comprenant des formes cristallines de monohydrate d'hydrochlorure de (r)-7-chloro-n-(quinuclidin-3-yl)benzo(b)thiophene-2-carboxamide
EP3029039A1 (fr) 2010-05-17 2016-06-08 Forum Pharmaceuticals Inc. Formulations pharmaceutiques comprenant des formes cristallines de monohydrate d'hydrochlorure de (r)-7-chloro-n-(quinuclidin-3-yl)benzo(b)thiophene-2-carboxamide
WO2012101060A1 (fr) 2011-01-27 2012-08-02 Novartis Ag Utilisation d'activateurs du récepteur nicotinique de l'acétylcholine alpha 7
WO2012124825A1 (fr) 2011-03-16 2012-09-20 Mitsubishi Tanabe Pharma Corporation Composés sulfonamides ayant une activité d'antagoniste de trpm8
WO2012127393A1 (fr) 2011-03-18 2012-09-27 Novartis Ag Combinaisons d'activateurs des récepteurs nicotiniques à l'acétylcholine alpha 7 et d'antagonistes des mglur5 destinées à être utilisées dans la dyskinésie induite par la dopamine dans la maladie de parkinson
EP2706854A4 (fr) * 2011-05-09 2014-12-03 Envivo Pharmaceuticals Inc Traitement de troubles cognitifs par certains agonistes du récepteur nicotinique alpha-7 en combinaison avec la nicotine
EP2706854A1 (fr) * 2011-05-09 2014-03-19 Envivo Pharmaceuticals, Inc. Traitement de troubles cognitifs par certains agonistes du récepteur nicotinique alpha-7 en combinaison avec la nicotine
WO2013002365A1 (fr) 2011-06-30 2013-01-03 東レ株式会社 Agent antiprurigineux
WO2013057687A2 (fr) 2011-10-20 2013-04-25 Novartis Ag Biomarqueurs prédictifs de la sensibilité au traitement par l'activateur du récepteur de l'acétylcholine nicotinique alpha 7
CN103159749A (zh) * 2011-12-13 2013-06-19 南京友杰医药科技有限公司 抗抑郁药维拉佐酮（vilazodone）的合成方法
WO2014091388A2 (fr) 2012-12-11 2014-06-19 Novartis Ag Biomarqueur de prédiction de la sensibilité à un traitement par un activateur du récepteur alpha 7 nicotinique de l'acétylcholine
WO2014111837A1 (fr) 2013-01-15 2014-07-24 Novartis Ag Utilisation d'agonistes des récepteurs nicotiniques de l'acétylcholine alpha 7
WO2014111751A1 (fr) 2013-01-15 2014-07-24 Novartis Ag Utilisation d'agonistes du récepteur nicotinique alpha 7 pour le traitement de la narcolepsie
WO2014111838A1 (fr) 2013-01-15 2014-07-24 Novartis Ag Utilisation d'agonistes du récepteur nicotinique alpha 7 de l'acétylcholine
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10584129B2 (en) 2013-06-04 2020-03-10 Janssen Pharmaceuticals Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11103506B2 (en) 2014-01-21 2021-08-31 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
EP3623371A1 (fr) 2014-12-16 2020-03-18 Axovant Sciences GmbH Composés amide de quinuclidine à substituants géminal en tant qu'agonistes des récepteurs nicotiniques de l'acétylcholine 7
WO2017060287A1 (fr) 2015-10-05 2017-04-13 Sandoz Ag Procédé pour la préparation d'encenicline à partir de chlorure d'acide 7-chloro-benzo[b]thiophène-2-carboxylique et de (r)-quinuclidin-3-amine en présence d'imidazole
WO2017060290A1 (fr) 2015-10-06 2017-04-13 Sandoz Ag Chlorhydrate d'encenicline cristallin
EP3153513A1 (fr) 2015-10-06 2017-04-12 Sandoz Ag Encenicline hydrochlorique crystallin
WO2018011611A1 (fr) * 2016-07-14 2018-01-18 Egis Gyógyszergyár Zrt. Sels pour la production de préparations pharmaceutiques

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AU2002358718A1 (en) 2003-07-15
US20120202842A1 (en) 2012-08-09
US7732477B2 (en) 2010-06-08
WO2003055878A8 (fr) 2003-08-21
US20050119325A1 (en) 2005-06-02
EP1461335B1 (fr) 2007-02-28
US8076355B2 (en) 2011-12-13
CA2471593C (fr) 2011-09-13
CA2471593A1 (fr) 2003-07-10
US8884017B2 (en) 2014-11-11
ES2282503T3 (es) 2007-10-16
EP1461335A1 (fr) 2004-09-29
US20100222378A1 (en) 2010-09-02
DE10164139A1 (de) 2003-07-10

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